title: Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial.
  
  
  METHODS
  Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m(2) daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m(2) daily for 5 days every 28 days). The primary end point was survival at 1 year.
  
  
  RESULTS
  Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival.
  
  
  CONCLUSIONS
  Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.
authors.affiliation: Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. brown.paul@mayo.edu
authors.forename: Paul D
authors.initials: PD
authors.lastname: Brown
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: Joon H
authors.initials: JH
authors.lastname: Uhm
authors.forename: Francois J
authors.initials: FJ
authors.lastname: Geoffroy
authors.forename: Robert
authors.initials: R
authors.lastname: Arusell
authors.forename: Gaspar
authors.initials: G
authors.lastname: Kitange
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: John W
authors.initials: JW
authors.lastname: Kugler
authors.forename: Roscoe F
authors.initials: RF
authors.lastname: Morton
authors.forename: Kendrith M
authors.initials: KM
authors.lastname: Rowland
authors.forename: Paul
authors.initials: P
authors.lastname: Mischel
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Scheithauer
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Caterina
authors.initials: C
authors.lastname: Giannini
authors.forename: Jan C
authors.initials: JC
authors.lastname: Buckner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015331:Cohort Studies; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018450:Disease Progression; D000069347:Erlotinib Hydrochloride; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage*; D011878:Radiotherapy / Q000379:methods*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D000077204:Temozolomide